Anthracyline antibiotics including doxorubicin, daunorubicin, and carminomycin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions including acute myeloblastic and lymphoblastic leukemias. Doxorubicin (also known as Adriamycin) is the subject of U.S. Pat. No. 3,590,028 and is a prescribed antineoplastic agent used in a number of chemotherapeutic treatments.
Certain undesirable side effects have limited the usefulness of known anthracyline antibiotics. One of their more serious side effects, however, is their cardiotoxicity which severely restricts the dosages and the frequency with which they can be administered and, in turn, limits their overall effectiveness as an antibiotic. Many of the other side effects which accompany the administration of these agents can be managed by administering other pharmaceutical agents in combination with them, however, the cardiopathic effects are not easily controlled or reversed.
In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop less toxic derivatives which can be administered in high, more effective dosages with greater frequency. The compounds disclosed in U.S. Pat. No. 4,201,773 to Horton et al are among anthracyline derivatives that have been proposed to have better therapeutic ratios than their naturally occurring counterparts. These compounds are derivatives of Adriamycin, daunomycin, and 4-demethoxydaunomycin in which the 3'amino group in the sugar moiety is substituted with a hydroxy group. Horton and Priebe also disclose a number of 2'-halo derivatives of Adriamycin, daunomycin and 4-demethoxydaunomycin in their U.S. Pat. No. 4,427,664.
One of the disadvantages of the aforementioned compounds is that they have relatively low solubility in water. This limits their usefulness and effectiveness because it often necessitates that they be administered in large volumes of infusate over a period of hours. Furthermore, in view of their low water solubility, the compounds are difficult to administer in amounts which would be effective in the treatment of some cancers.
Thus, there is a need for less toxic anthracyline antibiotics which are water soluble and readily absorbed into the blood stream.